Calmodulin Inhibitor W-7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes

Background— We have shown that the calmodulin inhibitor W-7 suppresses torsade de pointes (TdP) without shortening the QT interval, which is consistent with other findings that QT prolongation, per se, is insufficient to generate TdP. ECGs were analyzed from a well-characterized animal model of TdP to identify more reliable predictors of this life-threatening ventricular arrhythmia. Methods and Results— TdP was induced using methoxamine and clofilium in 12 of 14 rabbits pretreated with vehicle control, whereas pretreatment with W-7 (50 μmol/kg), an inhibitor of the intracellular Ca2+-binding protein calmodulin, significantly suppressed TdP induction (1 of 11 rabbits with TdP, P<0.001). W-7 did not affect heart rate, increases in QT intervals, or dispersion compared with measurements in vehicle-treated control animals. However, a progressive and significant increase in the ratio of U-wave to T-wave amplitude (UTA) occurred before TdP onset in control animals, and this was prevented by W-7. Conclusions— Sel...